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Halperin ST, ’t Hart BA, Luchicchi A, Schenk GJ. The Forgotten Brother: The Innate-like B1 Cell in Multiple Sclerosis. Biomedicines 2022; 10:606. [PMID: 35327408 PMCID: PMC8945227 DOI: 10.3390/biomedicines10030606] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/21/2022] [Accepted: 03/01/2022] [Indexed: 02/04/2023] Open
Abstract
Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS), traditionally considered a chronic autoimmune attack against the insulating myelin sheaths around axons. However, the exact etiology has not been identified and is likely multi-factorial. Recently, evidence has been accumulating that implies that autoimmune processes underlying MS may, in fact, be triggered by pathological processes initiated within the CNS. This review focuses on a relatively unexplored immune cell-the "innate-like" B1 lymphocyte. The B1 cell is a primary-natural-antibody- and anti-inflammatory-cytokine-producing cell present in the healthy brain. It has been recently shown that its frequency and function may differ between MS patients and healthy controls, but its exact involvement in the MS pathogenic process remains obscure. In this review, we propose that this enigmatic cell may play a more prominent role in MS pathology than ever imagined. We aim to shed light on the human B1 cell in health and disease, and how dysregulation in its delicate homeostatic role could impact MS. Furthermore, novel therapeutic avenues to restore B1 cells' beneficial functions will be proposed.
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Affiliation(s)
| | | | - Antonio Luchicchi
- Department of Anatomy and Neurosciences, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands; (S.T.H.); (B.A.’t.H.)
| | - Geert J. Schenk
- Department of Anatomy and Neurosciences, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HZ Amsterdam, The Netherlands; (S.T.H.); (B.A.’t.H.)
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Xue L, Clements-Egan A, Amaravadi L, Birchler M, Gorovits B, Liang M, Myler H, Purushothama S, Manning MS, Sung C. Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development. AAPS JOURNAL 2017; 19:1576-1586. [DOI: 10.1208/s12248-017-0153-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 07/31/2017] [Indexed: 12/16/2022]
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Pott MC, Frede N, Wanders J, Hammarström L, Glocker EO, Glocker C, Tahami F, Grimbacher B. Autoantibodies against BAFF, APRIL or IL21 - an alternative pathogenesis for antibody-deficiencies? BMC Immunol 2017. [PMID: 28651547 PMCID: PMC5485583 DOI: 10.1186/s12865-017-0217-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The ability of anti-cytokine antibodies to play a disease-causing role in the pathogenesis of immunodeficiencies is widely accepted. The aim of this study was to investigate whether autoantibodies against BAFF (important B cell survival signal), APRIL (important plasma cell survival signal), or Interleukin-21 (important cytokine for immunoglobulin class switch) present an alternative mechanism for the development of the following primary antibody deficiencies (PADs): common variable immune deficiency (CVID) or selective IgA deficiency (sIgAD). RESULTS Two hundred thirty-two sera from patients with PADs were screened for autoantibodies against cytokines by ELISA. Statistical data analysis yielded a significant difference (p < 0.01) between the healthy donor sera and both PAD cohorts. The analysis was deepened by subdividing the patient collective into groups with distinct B cell phenotypes but no significant differences were found. For selected sera with notable high ELISA-read outs functional analysis ensued. Anti-BAFF and anti-APRIL antibodies were further examined by a B cell survival assay, whilst the functional relevance of putative anti-IL-21 autoantibodies was investigated by means of a STAT3 phosphorylation assay. However, the results of these experiments revealed no discernible functional effect. CONCLUSION Whilst statistical analysis of ELISA results showed significant differences between patients and healthy controls, in our set of patients functional tests yielded no evidence for an involvement of autoantibodies against BAFF, APRIL, or IL-21 in the pathogenesis of CVID or sIgAD.
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Affiliation(s)
- Marian-Christopher Pott
- Centre for Chronic Immunodeficiency, Medical Centre University Hospital, Medical Faculty of Freiburg, Freiburg, Germany
| | - Natalie Frede
- Centre for Chronic Immunodeficiency, Medical Centre University Hospital, Medical Faculty of Freiburg, Freiburg, Germany
| | - Jennifer Wanders
- Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK
| | | | - Erik-Oliver Glocker
- Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany.,Institute of Laboratory Medicine, Brandenburg Hospital, Brandenburg Medical School, Brandenburg, Germany
| | - Cristina Glocker
- Centre for Chronic Immunodeficiency, Medical Centre University Hospital, Medical Faculty of Freiburg, Freiburg, Germany
| | - Fariba Tahami
- Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK
| | - Bodo Grimbacher
- Centre for Chronic Immunodeficiency, Medical Centre University Hospital, Medical Faculty of Freiburg, Freiburg, Germany. .,Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK.
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Gorovits B, Clements-Egan A, Birchler M, Liang M, Myler H, Peng K, Purushothama S, Rajadhyaksha M, Salazar-Fontana L, Sung C, Xue L. Pre-existing Antibody: Biotherapeutic Modality-Based Review. AAPS J 2016; 18:311-20. [PMID: 26821802 PMCID: PMC4779092 DOI: 10.1208/s12248-016-9878-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 01/20/2016] [Indexed: 01/12/2023] Open
Abstract
Pre-existing antibodies to biotherapeutic drugs have been detected in drug-naïve subjects for a variety of biotherapeutic modalities. Pre-existing antibodies are immunoglobulins that are either specific or cross-reacting with a protein or glycan epitopes on a biotherapeutic compound. Although the exact cause for pre-existing antibodies is often unknown, environmental exposures to non-human proteins, glycans, and structurally similar products are frequently proposed as factors. Clinical consequences of the pre-existing antibodies vary from an adverse effect on patient safety to no impact at all and remain highly dependent on the biotherapeutic drug modality and therapeutic indication. As such, pre-existing antibodies are viewed as an immunogenicity risk factor requiring a careful evaluation. Herein, the relationships between biotherapeutic modalities to the nature, prevalence, and clinical consequences of pre-existing antibodies are reviewed. Initial evidence for pre-existing antibody is often identified during anti-drug antibody (ADA) assay development. Other interfering factors known to cause false ADA positive signal, including circulating multimeric drug target, rheumatoid factors, and heterophilic antibodies, are discussed.
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Affiliation(s)
- Boris Gorovits
- Pfizer Worldwide Research & Development, PDM, 1 Burtt Rd, Andover, MA, USA.
| | - Adrienne Clements-Egan
- Janssen Research & Development, LLC (Johnson & Johnson), Welsh and McKean Roads, Spring House, PA, USA
| | - Mary Birchler
- Clinical Immunology, GlaxoSmithKline, King of Prussia, PA, USA
| | - Meina Liang
- MedImmune, Clinical Pharmacology and DMPK, Mountain View, CA, USA
| | - Heather Myler
- Bristol-Myers Squibb, Analytical & Bioanalytical Development, Princeton, NJ, USA
| | - Kun Peng
- Genentech, BioAnalytical Sciences, San Francisco, CA, USA
| | | | - Manoj Rajadhyaksha
- Regeneron Pharmaceuticals, Inc. Bioanalytical Sciences, Tarrytown, NY, USA
| | - Laura Salazar-Fontana
- DSAR, Project Standards and Innovation, Immunology and Biomarkers, Sanofi R&D, Framingham, MA, USA
| | - Crystal Sung
- DSAR, Clinical Laboratory Sciences, Sanofi R&D, Framingham, MA, USA
| | - Li Xue
- Pfizer Worldwide Research & Development, PDM, 1 Burtt Rd, Andover, MA, USA
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Cordy JC, Morley PJ, Wright TJ, Birchler MA, Lewis AP, Emmins R, Chen YZ, Powley WM, Bareille PJ, Wilson R, Tonkyn J, Bayliffe AI, Lazaar AL. Specificity of human anti-variable heavy (VH ) chain autoantibodies and impact on the design and clinical testing of a VH domain antibody antagonist of tumour necrosis factor-α receptor 1. Clin Exp Immunol 2015; 182:139-48. [PMID: 26178412 DOI: 10.1111/cei.12680] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2015] [Indexed: 12/20/2022] Open
Abstract
During clinical trials of a tumour necrosis factor (TNF)-R1 domain antibody (dAb™) antagonist (GSK1995057), infusion reactions consistent with cytokine release were observed in healthy subjects with high levels of a novel, pre-existing human anti-VH (HAVH) autoantibody. In the presence of HAVH autoantibodies, GSK1995057 induced cytokine release in vitro due to binding of HAVH autoantibodies to a framework region of the dAb. The epitope on GSK1995057 was characterized and dAbs with reduced binding to HAVH autoantibodies were generated; pharmacological comparability was determined in human in-vitro systems and in-vivo animal experiments. A Phase I clinical trial was conducted to investigate the safety and tolerability of the modified dAb (GSK2862277). A significant reduction in HAVH binding was achieved by adding a single alanine residue at the C-terminus to create GSK2862277. Screening a pool of healthy donors demonstrated a reduced frequency of pre-existing autoantibodies from 51% to 7%; in all other respects, GSK2862277 and the parent dAb were comparable. In the Phase I trial, GSK2862277 was well tolerated by both the inhaled and intravenous routes. One subject experienced a mild infusion reaction with cytokine release following intravenous dosing. Subsequently, this subject was found to have high levels of a novel pre-existing antibody specific to the extended C-terminus of GSK2862277. Despite the reduced binding of GSK2862277 to pre-existing HAVH autoantibodies, adverse effects associated with the presence of a novel pre-existing antibody response specific to the modified dAb framework were identified and highlight the challenge of developing biological antagonists to this class of receptor.
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Affiliation(s)
| | | | | | | | | | | | - Y Z Chen
- GlaxoSmithKline, King of Prussia, PA, USA
| | | | | | | | | | | | - A L Lazaar
- GlaxoSmithKline, King of Prussia, PA, USA
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Xu X, Ng SM, Hassouna E, Warrington A, Oh SH, Rodriguez M. Human-derived natural antibodies: biomarkers and potential therapeutics. FUTURE NEUROLOGY 2015; 10:25-39. [PMID: 25678860 DOI: 10.2217/fnl.14.62] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses ensures that normal immune activation contains non-self when tolerating self. Here we review the B-1 subset of lymphocytes which produce self-reactive antibodies. By analyzing the IgM class of natural antibodies that recognize antigens from the nervous system, we emphasize that natural antibodies are biomarkers of how the immune system monitors the host. The immune response activated against self can be detrimental when triggered in an autoimmune genetic background. In contrast, tuning immune activity with natural antibodies is a potential therapeutic strategy.
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Affiliation(s)
- Xiaohua Xu
- Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Sher May Ng
- School of Clinical Medicine, University Of Cambridge, Hills Rd, Cambridge CB2 0SP, UK
| | - Eamonn Hassouna
- Department of General Medicine, Charles University Hradec Kralove Faculty, Prague, Czech Republic
| | - Arthur Warrington
- Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Sang-Hyun Oh
- Laboratory of Nanostructures & Biosensing, Department of Electrical & Computer Engineering, University of Minnesota, Minneapolis, MN 55455, USA ; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - Moses Rodriguez
- Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA ; Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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Yamagiwa S, Kamimura H, Takamura M, Aoyagi Y. Autoantibodies in primary biliary cirrhosis: recent progress in research on the pathogenetic and clinical significance. World J Gastroenterol 2014; 20:2606-2612. [PMID: 24627596 PMCID: PMC3949269 DOI: 10.3748/wjg.v20.i10.2606] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 11/22/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of the small- and medium-sized intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMA) in the serum. AMA are detected in over 90% of patients with PBC, whereas their prevalence in the general population is extremely low, varying from 0.16% to 1%. Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens. Moreover, recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex, which is not observed in the serum of normal individuals. These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens. While it is currently generally accepted that AMA are the most specific serological markers of PBC, more than 60 autoantibodies have been investigated in patients with PBC, and some have previously been considered specific to other autoimmune diseases. This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC. Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research.
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Autoantibodies to Variable Heavy (VH) Chain Ig Sequences in Humans Impact the Safety and Clinical Pharmacology of a VH Domain Antibody Antagonist of TNF-α Receptor 1. J Clin Immunol 2013; 33:1192-203. [DOI: 10.1007/s10875-013-9915-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 06/06/2013] [Indexed: 01/13/2023]
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Brenden N, Madeyski-Bengtson K, Martinsson K, Svärd R, Albery-Larsdotter S, Granath B, Lundgren H, Lövgren A. A triple-transgenic immunotolerant mouse model. J Pharm Sci 2013; 102:1116-24. [PMID: 23316010 PMCID: PMC3594975 DOI: 10.1002/jps.23447] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/16/2012] [Accepted: 12/21/2012] [Indexed: 11/22/2022]
Abstract
Avoiding unwanted immunogenicity is of key importance in the development of therapeutic drug proteins. Animal models are of less predictive value because most of the drug proteins are recognized as foreign proteins. However, different methods have been developed to obtain immunotolerant animal models. So far, the immunotolerant animal models have been developed to assess one protein at a time and are not suitable for the assessment of combination products. Our aim was to develop an animal model for evaluating the impact of manufacturing and formulation changes on immunogenicity, suitable for both single protein and combination products. We constructed two lines of transgenic mice expressing the three human coagulation factors, II, VII, and X, by inserting a single vector containing the three coagulation factors encoding sequences separated by insulator sequences derived from the chicken beta-globin locus into the mouse genome. Immunization of transgenic mice from the two lines and their wild-type littermates showed that transgenic mice from both lines were immunotolerant to the expressed human coagulation factors. We conclude that transgenic mice immunotolerant to multiple proteins can be obtained, and that these mice are potentially useful as animal models in the assessment of immunogenicity in response to manufacturing changes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1116–1124, 2013
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Affiliation(s)
- Nina Brenden
- AstraZeneca, Safety Assessment, Södertälje, Sweden
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Batycka-Baran A, Flaig M, Molin S, Ruzicka T, Prinz JC. Etanercept-induced injection site reactions: potential pathomechanisms and clinical assessment. Expert Opin Drug Saf 2012; 11:911-21. [DOI: 10.1517/14740338.2012.727796] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Eaton MAW. How do we develop nanopharmaceuticals under open innovation? NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2011; 7:371-5. [PMID: 21703364 DOI: 10.1016/j.nano.2011.05.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 05/18/2011] [Indexed: 11/29/2022]
Abstract
It is incumbent on nanomedicine researchers to understand how to develop their ideas into commercial drugs; success to date has not been as good as funders would have liked. This article attempts to outline, perhaps for the first time, some of the expertise that the pharmaceutical sector has acquired to facilitate translation. It is hoped this explanation will start to improve the planning required at an early stage to develop nanopharmaceuticals and to encourage researchers and their institutions to devise a development plan.
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Lleo A, Invernizzi P, Gao B, Podda M, Gershwin ME. Definition of human autoimmunity--autoantibodies versus autoimmune disease. Autoimmun Rev 2010; 9:A259-A266. [PMID: 19963079 DOI: 10.1016/j.autrev.2009.12.002] [Citation(s) in RCA: 175] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The critical function of the immune system is to discriminate self from non-self. Tolerance against self-antigens is a highly regulated process and, in order to maintain it, the immune system must be able to distinguish self-reactive lymphocytes as they develop. The presence of autoantibodies is the consequence of breakdown of tolerance and, although they are an important serological feature of autoimmune diseases, their presence is not exclusive of these conditions. Antibodies against self-antigens are also found in cancer, during massive tissue damage and even in healthy subjects. Natural autoantibodies provide immediate protection against infection and also prevent inflammation by facilitating the clearance of oxidized lipids, oxidized proteins, and apoptotic cells; their role in development of autoimmunity is still unclear. Detection of serum autoantibodies in clinical practice has become more available to clinicians worldwide while providing a powerful diagnostic tool. This review discusses the clinical significance of autoantibodies, their pathogenic mechanisms in autoimmune diseases and, finally, illustrates the technology available for appropriate autoantibody detection.
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Affiliation(s)
- Ana Lleo
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
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Strohl WR, Knight DM. Discovery and development of biopharmaceuticals: current issues. Curr Opin Biotechnol 2009; 20:668-72. [DOI: 10.1016/j.copbio.2009.10.012] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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